Among excitatory amino acid receptor antagonists recognized for usefulness in the treatment of disorders are those that block N-methyl-D-aspartate (NMDA) receptors.
For example, heterocycles containing nitrogen, and having phosphonic acid and carboxylate substituents, are found in European Application Publication Numbers 0159889 and 0203891 and Australian Application Number 81455/87 which disclose utility for the treatment of nervous system disorders. The disorders disclosed which are responsive to blockade of the NMDA receptor include cerebral ischemia, muscular spasms (spasticity), convulsive disorders (epilepsy), and anxiety. These compounds, however, are readily distinguished from the compounds of the present invention both by the nitrogen containing heterocycles and by the various substituents thereon.
Aliphatic .alpha.-amino acids are disclosed in British Patent Numbers 2,104,078 and 2,156,818. The first of these, Number 2,104,078, includes 2-amino-7-phosphonoheptanoic acid (APH) disclosed for use in treating Huntington's disease, Alzheimer's disease, and certain forms of epilepsy as well as for use in the prevention of brain damage associated with stroke (see SCRIP #1067, Jan. 13, 1986, page 22). The second of these, 2,156,818, discloses usefulness for treating epilepsy, disorders associated with excess growth hormone (GH) or luteinizing hormone (LH) secretion, schizophrenia, depression, CNS degenerative disorders, and cerebral hypoxic conditions.
More particularly, U.S Pat. No. 4,657,899 discloses compounds of the formula ##STR1## wherein n and m=0, 1, 2, or 3 and X.sup.1 and X.sup.2 are the same or different and are selected from the group consisting of hydrogen, lower alkyl, halogen, --CH.dbd.CH--CH.dbd.CH--, amino, nitro, trifluoromethyl, or cyano, having activity as anticonvulsants, analgesics, and cognition enhancers through the antagonism of specific excitatory amino acid neurotransmitter receptors.
U.S. Pat. No. 4,761,405 teaches a cycloalkyl ring system having substiluents similar to U.S Pat. No. 4,657,899.
Additionally, .alpha.-amino acids on a carboxy-containing phenyl ring are disclosed in U.S. Pat. No. 4,065,572; British Patent Numbers 1,371,896 and 917,435 and Canadian Patent Number 748,446. However, these disclosures have different substituents.
The novel substituted .alpha.-amino acids of the present invention are not made obvious by these disclosures. In fact, clearly the disclosure of U.S. Pat. No. 4,657,899 is limited to a specific ortho positioning of phosphonic acid and amino acid residues on a phenyl ring. Such a limitation teaches away from the novel compounds of the present invention.
An understanding of the role of excitatory amino acids is expanded by J. C. Watkins, et al, in "Recent Advances in the Pharmacology of Excitatory Amino Acids", Excitatory Amino Acid Transmission: Neurology and Neurobiology, 24:19-26, Ed by Hicks, Lodge and McLennan, Publisher: Alan R Liss, Inc , New York, 1987.
An additional reference is now found to compounds, for example, for the treatment of diseases responding to a blockade of NMDA-sensitive receptors, in European Application Publication Number 0233154, of the formula ##STR2## showing a basic difference in that the phosphorus containing substituent and the amino/carboxy containing substituent are linked through a straight chain double bonded C.dbd.C linkage and not as substituents on a common aryl ring.
Then, on the other hand antagonists to the NMDA sensitive excitatory amino acid receptors are shown in U.S. Pat. No. 4,746,653, filed Feb. 28, 1986, to include substituted saturated pyridinyl ring systems common to both a phosphorus containing and carboxy or carboxy derivatized substituent.
More recently, the British Patent Application Number 2,198,134, filed Oct. 30, 1986, but not published before Jun. 8, 1988, teaches compounds useful for treating epilepsy including anticonvulsant activity shown from inhibition of NMDA in excitatory amino acid systems having the formula ##STR3## wherein R.sub.1 is a carboxy or carboxy containing analogue and y is a ##STR4## containing substiluent. However, the present invention is defined by a scope not taught within the broad disclosure of this application and, therefore, represents an advance not made obvious therein.
Although a related reference teaches "The Synthesis of p-Substituted D,L-Phenylglycines by the Amidoalkylation of Benzylchloride and N-Benzylbenzamide", Tetrahedron 33:2715-7 (1977) by D. Ben-Ishai, et al, it does not make obvious the use of the process for phosphonate containing derivatives.
Also known is the use of a 4-tetrazolylmethyl group on a piperidinyl-2-carboxylic acid moiety for use as an excitatory amino acid receptor antagonist as shown by a poster by Dr. P. L. Ornstein, et al, at the "First Princeton Drug Research Symposium" on May 21st to 23rd, 1989 and as disclosed in European Patent Application Number 330,353. However, no teaching is disclosed for the present from the piperidine of Ornstein's poster.
Finally, EP Publication Number 318935, a copending application, and European Patent Application Publication Number 313002 both disclose the use of a phosphonyl acid group.
Not all piperidinyl, pyridinyl or other heterocyclic ring systems are included in this Background as it is deemed such systems are different from the present invention compounds.